Imagine a lifetime of avoiding the sun — constantly wearing protective clothing and gear like face masks, hats, and gloves during all seasons, or even staying indoors and only going outside at night. That’s the current reality for patients with erythropoietic protoporphyria (EPP), a rare disorder caused by mutations to the FECH (ferrochelatase) gene.
The FECH gene encodes for the ferrochelatase enzyme that is crucial to the production of heme, the molecule containing iron that makes up part of hemoglobin in the blood. This leads to a buildup of PPIX (protoporphyrin IX) — a precursor to heme — in red blood cells. As PPIX moves through the skin’s blood vessels, it causes a phototoxic reaction that results in intense pain, swelling, burning, and potential disfigurement in patients. In addition, EPP often leads to gallstones, cholestasis, and liver damage as PPIX also accumulates in the hepatobiliary system.
Currently, there is no cure for EPP, and the FDA has only approved one treatment: the surgical implant Scenesse (afamelanotide) from CLINUVEL Pharmaceuticals. It works by stimulating melanin production to tan the skin and create a physical barrier to the sun, but like all other treatment approaches, it focuses on symptom relief and does not have any effect on the disease mechanism.
That could soon change. Disc Medicine recently announced submission of an NDA for accelerated approval of their daily oral pill, bitopertin, for patients 12 and older with EPP, including X-linked protoporphyria (XLP) caused by mutations to the ALAS2 (5-aminolevulinate synthase 2) gene. Disc’s submission is supported by data showing significant reductions in PPIX and improvements in patient symptoms and quality of life.
“Bitopertin is designed to reduce protoporphyrin IX in the blood, which is the photoreactive molecule that directly causes pain reactions and hepatobiliary complications in EPP/XLP patients, so it is the first treatment with the potential to address the underlying cause of disease,” John Quisel, CEO of Disc, told DDN.
Blocking a protein to protect the skin
Previously, the FDA granted bitopertin both Orphan Drug Designation and Rare Pediatric Disease Designation. The FDA’s decision on whether to accept Disc’s NDA submission for review is expected in December. If granted priority review, the FDA’s approval decision would be expected in June 2026.
If bitopertin is approved, it could mark another non-gene therapy approval for a rare genetic disease during a year that has seen the FDA repeatedly delay or reject gene-editing treatments. It would also signal the continued strength of orphan drugs in the regulatory sphere. Last year alone, over 50 percent of the FDA’s novel drug approvals were orphan drugs, and they’re expected to make up 20 percent of the global prescription market by 2030.
As an investigational small molecule drug, bitopertin works by inhibiting GlyT1 (gylcine transporter 1) and reducing the amount of glycine available for heme synthesis, which then leads to a decrease in downstream PPIX.
It is the first treatment with the potential to address the underlying cause of disease.
– John Quisel, Disc Medicine
Based on data Disc’s Phase 2 AURORA and BEACON trials presented at the American Society for Hematology (ASH) meeting, bitopertin was shown to reduce PPIX by 50 percent and 40 percent, respectively. Compared to placebo in the AURORA trial, bitopertin led to a 75 percent reduction in phototoxic reactions, and led to a significant improvement in the quality of life according to the Patient Global Impression of Change (PGIC) scale.
The drug was also tolerated well with mild to moderate side effects. The most common treatment-related side effect was dizziness, though Quisel noted that it was generally transient.
Bitopertin’s past and future
Bitopertin also has significant safety data from over 4,000 participants in previous clinical trials led by Roche. In 2021, Disc gained global rights to bitopertin following its failure in Phase 3 trials aiming to treat individuals with schizophrenia. In that context, the goal was for bitopertin to inhibit GlyT1 and increase glycine levels to improve the function of N-methyl-D-aspartate (NMDA) receptors in the brain.
This would have been a novel drug mechanism, as all approved drugs for schizophrenia targeted the dopamine 2 receptor for over 70 years until the recent approval of Bristol-Myers Squibb’s Cobenfy last year. Yet, this remains a tough market within the neuroscience therapeutics space, with Cobenfy failing a Phase 3 trial earlier this year as an adjunctive treatment, leaving the drug’s future uncertain.
Bitopertin could have future indications beyond EPP as well. The National Institutes of Health (NIH) is currently studying its use in the rare blood disorder Diamond-Blackfan anemia (DBA), in which anemia arises because the bone marrow does not make enough red blood cells. “Glycine is the first step in the heme biosynthesis pathway, so modulating its availability in [red blood cells] could have the potential to address diseases associated with toxic levels of porphyrins (heme precursors), heme, or other processes downstream of the heme synthesis pathway,” Quisel told DDN.
For now, Disc hopes to see bitopertin’s approval in 2026 for EPP. “This NDA submission represents a pivotal moment not just for Disc but for the EPP community as we seek to provide patients with a treatment option that has the potential to address the underlying cause of disease,” Quisel said in the press release.
